Eicosapentaenoic acid promotes apoptosis in Ramos cells via activation of caspase‐3 and ‐9

Abstract

Eicosapentaenoic acid (EPA; 20:5n-3) may reduce the cell number in cultured leukemia/lymphoma cells owing to reduced cell proliferation, induction of cell death, or a combination of these processes. EPA has been shown to promote apoptosis in Ramos cells, and our present study was focused on a possible cell cycle arrest and the pathways by which the apoptotic process is induced. Apoptosis may proceed along the intrinsic (mitochondrial) or the extrinsic (death receptor) pathway, which are mediated via different caspases. Caspases are a class of homologous cysteine proteases recognized as pivotal mediators of apoptosis. We investigated whether EPA affects progression of the cell cycle or promotes apoptosis directly. By incorporation of [3H]thymidine and [3H]valine, we showed that DNA, as well as protein synthesis, was reduced after incubation of Ramos cells with EPA for 6 h. We monitored cell cycle distribution by 5-bromo-2'-deoxyuridine staining and observed no cell cycle arrest in the EPA-incubated cells. Incubation of cells with EPA caused PS-flipping, as demonstrated by annexin V-binding (flow cytometry), and cleavage of poly(ADP-ribose) polymerase measured by Western blot analysis. Furthermore, we observed increased activity of caspase-3 and -9, but not of caspase-8. Whereas inhibitors of caspase-3 and -9 reduced EPA-induced apoptosis, inhibition of caspase-8 did not. This suggests that EPA may promote apoptosis via the intrinsic pathway in Ramos cells. Thus, the reduction in cell number can be explained by a direct apoptotic effect of EPA rather than via cell cycle arrest.

Summer Student Breast Cancer Research Training Program

“…EPA can be converted to DHA and therefore, it can have effects similar to DHA on cell cycle arrest. Indeed several investigators have demonstrated that EPA also blocks cell cycle progression and induces apoptosis in Ramos cells [98], squamous cell carcinoma [99], vascular smooth muscle cells [75], HT29 colonic cells [100], and pancreatic PaCa-2 cancer cells [101]. In most cases the results are consistent with our finding of growth arrest in the S phase of cell cycle progression [75,100,101] through inhibition of cdk2 activities [75].…”

Docosahexaenoic acid induces apoptosis in lung cancer cells by increasing MKP-1 and down-regulating p-ERK1/2 and p-p38 expression

“…Both intrinsic and extrinsic apoptosis pathways have been found to be activated by n-3 PUFAs in different kinds of normal and tumor cells. In particular, it was shown that DHA was able to alter the expression and the activity of caspase-8 and -9 in colon cancer and HL-60 lymphoma cells [59,60]. Moreover, EPA induced an increased activity of caspase-3 and -9 in the lymphoma Ramos cell line [59] and dietary n-3 PUFAs were able to decrease BCL-2 and increase FAS-ligand expression in normal splenic lymphocytes of Balb/c mice [61].…”

Differential Effects of Delivery of Omega-3 Fatty Acids to Human Cancer Cells by Low-Density Lipoproteins versus Albumin

“…Consistent with previous reports (6,8,28), cell growth was inhibited by EPA-BSA, but no induction of apoptosis was observed. Although n-3 FA-associated apoptosis has been reported in animal models (29,30), in lymphoma (31,32), and colon cancer cells (33,34), data with breast cancer cells are sparse. Chamras et al (28) failed to detect apoptosis in MCF-7 cells treated with EPA and DHA methyl esters.…”